The present invention is concerned with the finding that farnesyl protein transferase inhibitors have radiosensitizing properties which makes them useful for preparing a pharmaceutical composition for administration before, during or after irradiation of a tumor for treating cancer in vivo.
WO-97/21701 describes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (III) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by 
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl,
or a radical of formula xe2x80x94Alk1xe2x80x94C(xe2x95x90O)xe2x80x94R9, xe2x80x94Alk1xe2x80x94S(O)xe2x80x94R9 or xe2x80x94Alk1xe2x80x94S(O)2xe2x80x94R9, wherein Alk1 is C1-6alkanediyl,
R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;
R2, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or
when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-2),
xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-S), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-6);
R4 and R5 each independently are hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar2oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or
when on adjacent positions R6 and R7 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-1), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-2);
R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, or a radical of formula
xe2x80x94Oxe2x80x94R10xe2x80x83xe2x80x83(b-1),
xe2x80x94Sxe2x80x94R10xe2x80x83xe2x80x83(b-2),
xe2x80x94Nxe2x80x94R11R12xe2x80x83xe2x80x83(b-3),
wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical or formula xe2x80x94Alk2xe2x80x94OR13 or xe2x80x94Alk2xe2x80x94NR14R15;
R11 is hydrogen, C1-12alkyl, Ar1 or Ar2C1-6alkyl;
R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkylcarbonylC1-6alkyl, a natural amino acid, Ar1carbonyl, Ar2C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula xe2x80x94Alk2xe2x80x94OR13 or xe2x80x94Alk2xe2x80x94NR14R15;
wherein Alk2 is C1-6alkanediyl;
xe2x80x83R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar2C1-6alkyl;
xe2x80x83R14 is hydrogen, C1-6alkyl, Ar1 or Ar2C1-6alkyl;
xe2x80x83R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1or Ar2C1-6alkyl;
R17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar1;
R18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;
R19 is hydrogen or C1-6alkyl;
Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo; and
Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.
WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by 
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl,
or a radical of formula xe2x80x94Alk1xe2x80x94C(xe2x95x90O)xe2x80x94R9, xe2x80x94Alk1xe2x80x94S(O)xe2x80x94R9 or xe2x80x94Alk1xe2x80x94S(O)2xe2x80x94R9, wherein Alk1 is C1-6alkanediyl,
R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;
R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or
when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-2),
xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-5), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-6);
R4 and R5 each independently are hydrogen, Ar1, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Ar2oxy;
R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, hydroxycarbonylC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, Ar1, Ar2C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl;
R10 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;
R11 is hydrogen or C1-6alkyl;
Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo;
Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.
PCT/EP98/01296, filed Mar. 3, 1998, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII) 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
xe2x80x94Axe2x80x94 is a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-2),
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-3),
xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-4),
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-5),
xe2x80x94CH2xe2x80x94Sxe2x80x94xe2x80x83xe2x80x83(a-6),
xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94xe2x80x83xe2x80x83(a-7),
xe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-8),
xe2x80x94Nxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-9), or
xe2x80x94COxe2x80x94NHxe2x80x94xe2x80x83xe2x80x83(a-10);
wherein optionally one hydrogen atom may be replaced by C1-4alkyl or Ar1;
R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar2, Ar2xe2x80x94C1-6alkyl, Ar2-oxy, Ar2xe2x80x94C1-6alkyloxy;
or when on adjacent positions R1 and R2 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(b-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(b-2),
xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(b-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(b-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(b-5), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(b-6);
R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar3-oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl, trihalomethoxy, or
when on adjacent positions R3 and R4 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(C-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-2), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-3);
R5 is a radical of formula 
xe2x80x83wherein R13 is hydrogen, halo, Ar4, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R14 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;
R6 is hydrogen, hydroxy, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar5, Ar5xe2x80x94C1-6alkyloxyC1-6alkyl; or a radical of formula
xe2x80x94Oxe2x80x94R7xe2x80x83xe2x80x83(e-1),
xe2x80x94Sxe2x80x94R7xe2x80x83xe2x80x83(e-2),
xe2x80x94Nxe2x80x94R8R9xe2x80x83xe2x80x83(e-3),
wherein R7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar6, Ar6xe2x80x94C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula xe2x80x94Alkxe2x80x94OR10 or xe2x80x94Alkxe2x80x94NR11R12;
R8 is hydrogen, C1-6alkyl, Ar7 or Ar7xe2x80x94C1-6alkyl;
R9 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar8, Ar8xe2x80x94C1-6alkyl, C1-6alkylcarbonylC1-6alkyl, Ar8-carbonyl, Ar8xe2x80x94C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula xe2x80x94Alkxe2x80x94OR10 or xe2x80x94Alkxe2x80x94NR11R12;
wherein Alk is C1-6alkanediyl;
xe2x80x83R11 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar9 or Ar9xe2x80x94C1-6alkyl;
xe2x80x83R11 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar10 or Ar10xe2x80x94C1-6alkyl;
xe2x80x83R12 is hydrogen, C1-6alkyl, Ar11 or Ar11xe2x80x94C1-6alkyl; and
xe2x80x83Ar1 to Ar11 are each independently selected from phenyl; or phenyl substituted with halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
PCT/EP98/02357, filed Apr. 17, 1998, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VIII) 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar1C1-6alkyl, Ar1oxy or Ar1C1-6alkyloxy;
R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar1oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl or trihalomethoxy;
R5 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar1, Ar1C1-6alkyloxyC1-6alkyl; or a radical of formula
xe2x80x94Oxe2x80x94R10xe2x80x83xe2x80x83(a-1),
xe2x80x94Sxe2x80x94R10xe2x80x83xe2x80x83(a-2),
xe2x80x94Nxe2x80x94R11R12xe2x80x83xe2x80x83(a-3),
wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula xe2x80x94Alkxe2x80x94OR13 or xe2x80x94Alkxe2x80x94NR14R15;
R11 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;
R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkylcarbonylC1-6alkyl, Ar1carbonyl, Ar1C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula xe2x80x94Alkxe2x80x94OR13 or xe2x80x94Alkxe2x80x94NR14R15;
wherein Alk is C1-6alkanediyl;
xe2x80x83R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar1C1-6alkyl;
xe2x80x83R14 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;
xe2x80x83R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar1C1-6alkyl;
R6 is a radical of formula 
wherein R16 is hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R17 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;
R7 is hydrogen or C1-6alkyl provided that the dotted line does not represent a bond;
R8 is hydrogen, C1-6alkyl or Ar2CH2 or Het1CH2;
R9 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo; or
R8 and R9 taken together to form a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-1),
xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(c-2),
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(c-3),
xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-4), or
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-5);
Ar1 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;
Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl; and
Het1 is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
Other useful farnesyl protein transferase inhibitors have the structure 
These farnesyl protein transferase inhibitors decrease the growth of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by inhibiting angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Consequently, treatment with these inhibitors suppresses solid tumor growth in vivo at least in part by inhibiting angiogenesis. This being the case, one could expect that treatment with these compounds could result in hypoxic tumors, thereby inducing or causing increased radio-resistance.
Unexpectedly, we have now found that that does not happen. On the contrary, it appears that administration of a farnesyl protein transferase inhibitor as described hereinbefore sensitizes tumor cells in vivo to irradiation or ionizing radiation and moreover, resensitizes radioresistant cells. Thus, farnesyl protein transferase inhibitors are useful as in vivo radiosensitizing (radiation-sensitizing or radiation-potentiating) agents.
The present invention is concerned with the use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor for treating cancer in vivo.
In particular, the present invention is concerned with the use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor for treating cancer in vivo, wherein said farnesyl protein transferase inhibitor is an (imidazoly-5-yl)methyl-2-quinolinone derivative of formula (I), or a compound of formula (II) or (III) which is metabolized in vivo to the compound of formula (I), said compounds being represented by 
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl,
or a radical of formula xe2x80x94Alk1xe2x80x94C(xe2x95x90O)xe2x80x94R9, xe2x80x94Alk1xe2x80x94S(O)xe2x80x94R9 or xe2x80x94Alk1xe2x80x94S(O)2xe2x80x94R9, wherein Alk1 is C1-6alkanediyl,
R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;
R2, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or
when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-2),
xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-5), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-6);
R4 and R5 each independently are hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar2oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or
when on adjacent positions R6 and R7 taken together may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-1), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-2);
R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, or a radical of formula
xe2x80x94Oxe2x80x94R10xe2x80x83xe2x80x83(b-1),
xe2x80x94Sxe2x80x94R10xe2x80x83xe2x80x83(b-2),
xe2x80x94Nxe2x80x94R11R12xe2x80x83xe2x80x83(b-3),
wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical or formula xe2x80x94Alk2xe2x80x94OR13 or xe2x80x94Alk2xe2x80x94NR14R15;
R11 is hydrogen, C1-12alkyl, Ar1 or Ar2C1-6alkyl;
R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkylcarbonylC1-6alkyl, a natural amino acid, Ar1carbonyl, Ar2C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula xe2x80x94Alk2xe2x80x94OR13 or xe2x80x94Alk2xe2x80x94NR14R15;
wherein Alk2 is C1-6alkanediyl;
xe2x80x83R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar2C1-6alkyl;
xe2x80x83R14 is hydrogen, C1-6alkyl, Ar1 or Ar2C1-6alkyl;
xe2x80x83R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar2C1-6alkyl;
R17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar1;
R18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;
R19 is hydrogen or C1-6alkyl;
Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo; and
Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.
In formulas (I), (II) and (III), R4 or R5 may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R4 or R5 and the meaning of R4 and R5 when bound to the nitrogen is limited to hydrogen, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl, C1-6alkylS(O)2C1-6alkyl.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-6alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C1-8alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-6alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; C1-12alkyl again encompasses C1-8alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; C1-16alkyl again encompasses C1-12alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentadecyl and hexadecyl; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof. The term xe2x80x9cC(xe2x95x90O)xe2x80x9d refers to a carbonyl group, xe2x80x9cS(O)xe2x80x9d refers to a sulfoxide and xe2x80x9cS(O)2xe2x80x9d to a sulfon. The term xe2x80x9cnatural amino acidxe2x80x9d refers to a natural amino acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.
The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulas (I), (II) and (III) are able to form. The compounds of formulas (I), (II) and (III) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The compounds of formulas (I), (II) and (III) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The terms acid or base addition salt also comprise the hydrates and the solvent addition forms which the compounds of formulas (I), (II) and (III) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomeric forms of compounds of formulas (I), (II) and (III), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formulas (I), (II) and (III) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereo-chemically isomeric forms of the compounds of formulas (I), (II) and (III) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formulas (I), (II) and (III) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formulas (I), (II) and (III)xe2x80x9d is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.
Preferably the substituent R18 is situated on the 5 or 7 position of the quinolinone moiety and substituent R19 is situated on the 8 position when R18 is on the 7-position.
Interesting compounds are these compounds of formula (I) wherein X is oxygen.
Also interesting compounds are these compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond.
Another group of interesting compounds are those compounds of formula (I) wherein R1 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, or a radical of formula xe2x80x94Alk1xe2x80x94C(xe2x95x90O)xe2x80x94R9, wherein Alk1 is methylene and R9 is C1-8alkylamino substituted with C1-6alkyloxycarbonyl.
Still another group of interesting compounds are those compounds of formula (I) wherein R3 is hydrogen or halo; and R2 is halo, C1-6alkyl, C2-6alkenyl, C1-6alkyloxy, trihalomethoxy or hydroxyC1-6alkyloxy.
A further group of interesting compounds are those compounds of formula (I) wherein R2 and R3 are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3).
A still further group of interesting compounds are those compounds of formula (I) wherein R5 is hydrogen and R4 is hydrogen or C1-6alkyl.
Yet another group of interesting compounds are those compounds of formula (I) wherein R7 is hydrogen; and R6 is C1-6alkyl or halo, preferably chloro, especially 4-chloro.
A particular group of compounds are those compounds of formula (I) wherein R8 is hydrogen, hydroxy, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, imidazolyl, or a radical of formula xe2x80x94NR11R12 wherein R11 is hydrogen or C1-12alkyl and R12 is hydrogen, C1-6alkyl, C1-6alkyloxy, hydroxy, C1-6alkyloxyC1-6alkylcarbonyl, or a radical of formula xe2x80x94Alk2xe2x80x94OR13 wherein R13 is hydrogen or C1-6alkyl.
Preferred compounds are those compounds wherein R1 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, or a radical of formula xe2x80x94Alk1xe2x80x94C(xe2x95x90O)xe2x80x94R9, wherein Alk1 is methylene and R9 is C1-8alkylamino substituted with C1-6alkyloxycarbonyl; R2 is halo, C1-6alkyl, C2-6alkenyl, C1-6alkyloxy, trihalomethoxy, hydroxyC1-6alkyloxy or Ar1; R3 is hydrogen; R4 is methyl bound to the nitrogen in 3-position of the imidazole; R5 is hydrogen; R6 is chloro; R7 is hydrogen; R8 is hydrogen, hydroxy, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, imidazolyl, or a radical of formula xe2x80x94NR11 R12 wherein R11 is hydrogen or C1-12alkyl and R12 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkylcarbonyl, or a radical of formula xe2x80x94Alk2xe2x80x94OR13 wherein R13 is C1-6alkyl; R17 is hydrogen and R18 is hydrogen.
Most preferred compounds are
4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-ethyl-2(1H)-quinolinone;
6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;
6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;
6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone monohydrochloride.monohydrate;
6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,
6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propyl-phenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt; and in particular
(+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone (Compound 75 in Table 1 of the Experimental Part); or a pharmaceutically acceptable acid addition salt thereof.
Farnesyl protein transferase inhibitors can be formulated into pharmaceutical compositions as known in the art; for the compounds of formulas (I), (II) and (III) suitable examples can be found in WO-97/21701. To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with pharmaceutically acceptable carriers, which may take a wide variety of forms depending on the form of preparation desired for administration.
These pharmaceutical compositions are, desirably as unitary dosage forms, administered orally, parenterally, percutaneously, rectally or topically for systemic action, which is preferred, or for topical action. In case of oral liquid pharmaceutical preparations, comprising solutions, suspensions, syrups, elixirs and emulsions, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, may be employed, whereas in case of oral solid pharmaceutical preparations, comprising powders, pills, capsules and tablets, excipients such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously employed. In case of injectable pharmaceutical compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, such as semipolair solvents, may be included, for example, to aid solubility. Examples of carriers for injectable solutions comprise saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of the aforementioned formulas may also be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. For the preparation of injectable suspensions, appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment or as a gel. In case of pharmaceutical compositions for rectal administration, any of the usual excipients may be employed, comprising fat based and water soluble excipients, optionally combined with suitable additives, such as suspending or wetting agents. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, lotions, shampoos, tinctures, pastes, ointments, salves, ovules, powders, inhalations, nose sprays, eye drops and the like. Semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used, but application of said compositions may be, for example, also by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray or drops.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, suppositories, ovules, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Preferably, a therapeutically effective amount of the pharmaceutical composition comprising a farnesyl protein transferase inhibitor is administered orally or parenterally. Said therapeutically effective amount is the amount that effectively sensitizes a tumor in a host to irradiation. On the basis of the current data, it appears that the pharmaceutical composition comprising (+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (compound 75) as the active ingredient can be administered orally in an amount of from 10 up to 1500 mg/m2 daily, either as a single dose or subdivided into more than one dose, or more particularly in an amount of from 100 to 1000 mg/m2 daily.
Irradiation means ionizing radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today. The irradiation of the tumor by radionuclides can be external or internal.
Preferably, the administration of the pharmaceutical composition commences up to one month, in particular up to 10 days or a week, before the irradiation of the tumor. Additionally, it is advantageous to fractionate the irradiation of the tumor and maintain the administration of the pharmaceutical composition in the interval between the first and the last irradiation session.
The amount of farnesyl protein transferase inhibitor, the dose of irradiation and the intermittence of the irradiation doses will depend on a series of parameters such as the type of tumor, its location, the patients"" reaction to chemo- or radiotherapy and ultimately is for the physician and radiologists to determine in each individual case.
The present invention also concerns a method of cancer therapy for a host harboring a tumor comprising the steps of
administering a radiation-sensitizing effective amount of a farnesyl protein transferase inhibitor before, during or after
administering radiation to said host in the proximity to the tumor.
Examples of tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt""s lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma, kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.